Obesity, a global epidemic, is more prevalent among veterans than in the general public. The magnitude of this epidemic is highlighted by a recent RFA for obesity-related research (IL-12-2005-003) by the Department of Veteran Affairs. Despite vigorous attempts, to date no suitable anti-obesity drugs are available. We therefore propose investigations towards the development of anti-obesity drugs based on endogenous orexigenic and satiety signals. In this regard, neuropeptide Y (NPY), most abundant peptide in the mammalian brain, has been characterized as the most powerful orexigenic peptide isolated to date. Moreover, hypothalamic NPY also mediates the actions of leptin and ghrelin on food intake and metabolism. In addition, NPY knock-out ob/ob mice ate less and exhibited increased energy expenditure, and therefore, were less obese. Patients with anorexia nervosa and bulimia had abnormal levels of NPY in the cerebrospinal fluid, which returned to normal on treatment. Thus, NPY constitutes a critical component of neuropeptidergic circuitary controlling food intake and energy expenditure. On the other hand NPY homologous peptides, peptide YY (PYY) and pancreatic polypeptide (PP), released postprandially by the intestine act as powerful satiety signals via shutting off the actions and/or synthesis of central orexigenic signals including NPY. Therefore, the four G-protein coupled receptors denoted as Y1, Y2, Y4, and Y5 mediating the actions of NPY, PYY and PP on food intake remain obvious targets for the development of anti-obesity drugs. Our investigations towards this goal have already led to the identification of lower molecular weight tri-peptide (Y5), pentapeptide (Y1 and Y4) and decapeptide (Y2) motifs for interaction with NPY receptors. We now hypothesize that structure-activity studies with these compounds will lead to the development of highly potent and receptor selective analogs which would have great significance for fundamental investigations and perhaps for clinical utility, especially to treat obesity. This hypothesis will be investigated through three specific aims: 1) Design and synthesis of long acting and potent receptor selective ligands; 2) Investigation of the in vitro properties of the ligands using cell lines specifically expressing individual Y receptors; 3) Investigating in vivo effects of receptor specific ligands on food intake and metabolism in rats. Potential Impact on Veterans Health Care: The proposed study may lead to the development of novel class of anti-orexigenic and satiety drugs. Treatment with these drugs together with diet and exercise can be expected to alleviate the overweight problem among the veterans. In addition, NPY have also been implicated NPY in the pathophysiology of anxiety, depression and PTSD, conditions highly prevalent among the veterans. Therefore, our studies may eventually lead to the betterment of the quality of life of not only the overweight veterans, but also those with a variety of psychiatry disorders. This could enhance recall opportunities and reduce the burden on the Veterans Health Care cost.